The ubiquitin proteasome system (UPS) consists of a cascade of enzymatic steps that are initiated by E1 ubiquitin activating enzyme which after loading two ubiquitin molecules transfers one to E2 conjugating enzymes that in concert with a large number (˜1000) of protein specificity conferring E3 ligases attach ubiquitin chains to target proteins. Finley et al., Cell, 116(2 Suppl):S29-32, 22 p following S32 (2004). Depending on how ubiquitin is attached this can either alter cellular localization and function or target the protein for degradation in the proteasome. Deubiquitinases counter-regulate by removing ubiquitin tags.
Studies in multiple myeloma (MM) have established the value of targeting the UPS in cancer therapy. Richardson et al., N Engl J Med, 348(26), 2609-2617 (2003). Moreover, the proteasome inhibitor bortezomib (BTZ) was shown to improve outcome in the setting of high risk cytogenetic findings. Avet-Loiseau et al., J Clin Oncol, 28(30):4630-4634 (2010); Neben et al., Blood, 119(4):940-948 (2012). Recent findings suggest that the other main class of “novel drugs”, IMiDs™ also exploits the UPS, but in an opposite and less broad fashion. By increasing the affinity of the substrate recognition domain of the cereblon/CRL4 E3 ligase for Ikaros transcription factors, lenalidomide and related drugs lead to their degradation. Since these transcription factors activate production of the MM survival factor IRF4 in MM and repress IL2 transcription in T cells, their proteasomal degradation results in anti-MM and immune-stimulatory effects. Kronke et al., Science, 343(6168), 301-305 (2014). Evidence from clinical trials suggests that high cereblon expression may be required for full response and survival benefit from IMiDs™, supporting on the one hand a strategy aimed at increasing protein degradation but on the other hand revealing limitations of distal targets.
MM is characterized by transformation at or after activation of the plasma cell program in B-cells which not only maintains production of diagnostic antibodies but also entails broad survival promoting effects of its main initiator, IRF4, which is augmented in expression through a “vicious” positive feedback loop with c-MYC, and supported in survival signaling by constitutive B-cell receptor independent NF-κB activation. Furthermore, in almost half of MM patients translocation of an oncogene into the proximity of the IGH enhancer provides another link to the plasma cell program. While each of these survival proteins lend themselves to direct or indirect targeting, one way to reach them all and thereby limit adaptive escape mechanisms is by interfering with the very feature that sets MM apart from other cells: Excessive protein synthesis required for antibody production and for rapid re-supply of critical proteins with high turn-over like c-MYC.
Protein disulfide isomerase (PDI) is responsible for post-translational folding of newly synthesized proteins through reductase, oxidase, isomerase, and chaperone functions it exerts in the endoplasmic reticulum. While tried in other cancers with some success the plasma cell program should make MM exquisitely sensitive to PDI inhibition but so far this has not been attempted and testing in other cancers, thrombotic and neurodegenerative disease has so far not yielded PDI inhibitors that entered the clinic.
High risk MM affects about 20% of MM patients and reduces their life expectancy to 2-3 years. It can be classified according to clinical findings or genetic aberrations in MM cells. Although the impact of most mutations found in MM by whole genome or exome sequencing is incompletely understood, specific mutations like del 17p13, translocation 14;16, or gene expression profiles that correlate with chromosome 1 abnormalities generally predict more strongly for worse outcome than clinical factors. Other MM specific characteristics, like the number of sub-clones at diagnosis or their genomic instability increase plasticity of the neoplastic process and are probably even more important determinants of poor prognosis. Fonseca R, Monge J., Semin Oncol, 40(5), 554-566 (2013). Activation of multiple survival programs in one clone, switch between clones, and intraclonal development of new survival strategies probably converge in the highest risk myelomas.
Despite progress in the treatment of multiple myeloma, it remains an incurable cancer and most patients with bortezomib refractory disease and previous treatment with IMiDs™thalidomide and/or lenalidomide experience short progression-free and overall survival of 6 and 9 months, respectively. Kumar et al., Leukemia, 26(5), 1153 (2012). Although new treatments have been approved for these patients and more agents are in development, none of them is expected to be curative and they ultimately all select for even more resistant clones with stronger survival mechanisms.